rs213950

Variant names:

• chr7-117559479-G-A
• rs213950
• NM_000492.4:c.1408G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1408G>A​(p.Val470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,597,726 control chromosomes in the GnomAD database, including 164,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V470G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.56 (26569 hom., cov: 31)
  • Exomes 𝑓: 0.43 (137735 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 2.57
• Publications: 249 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117559480-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3336635.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=9.284489E-7).
• BP6: Variant 7-117559479-G-A is Benign according to our data. Variant chr7-117559479-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1408G>A	p.Val470Met	missense_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1254C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1408G>A	p.Val470Met	missense_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84573 AN: 151846 Hom.: 26503 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.475 AC: 119239 AN: 251166 AF XY: 0.464

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.427 AC: 616894 AN: 1445762 Hom.: 137735 Cov.: 30 AF XY: 0.427 AC XY: 307171 AN XY: 720158

African (AFR) AF: 0.881 AC: 29129 AN: 33072

American (AMR) AF: 0.521 AC: 23304 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7363 AN: 26044

East Asian (EAS) AF: 0.406 AC: 16061 AN: 39550

South Asian (SAS) AF: 0.475 AC: 40761 AN: 85900

European-Finnish (FIN) AF: 0.547 AC: 29100 AN: 53222

Middle Eastern (MID) AF: 0.387 AC: 2220 AN: 5736

European-Non Finnish (NFE) AF: 0.403 AC: 442722 AN: 1097698

Other (OTH) AF: 0.438 AC: 26234 AN: 59844

GnomAD4 genome AF: 0.557 AC: 84699 AN: 151964 Hom.: 26569 Cov.: 31 AF XY: 0.561 AC XY: 41636 AN XY: 74256

African (AFR) AF: 0.861 AC: 35759 AN: 41512

American (AMR) AF: 0.518 AC: 7908 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3468

East Asian (EAS) AF: 0.419 AC: 2161 AN: 5158

South Asian (SAS) AF: 0.488 AC: 2352 AN: 4820

European-Finnish (FIN) AF: 0.562 AC: 5917 AN: 10526

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28165 AN: 67914

Other (OTH) AF: 0.510 AC: 1076 AN: 2110

Alfa AF: 0.444 Hom.: 71118

Bravo AF: 0.564

TwinsUK AF: 0.403 AC: 1493

ALSPAC AF: 0.391 AC: 1507

ESP6500AA AF: 0.850 AC: 3747

ESP6500EA AF: 0.468 AC: 4026

ExAC AF: 0.483 AC: 58619

Asia WGS AF: 0.527 AC: 1834 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.390

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 27, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cystic fibrosis Benign:7

Mar 17, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 1990

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2023

Payam Genetics Center, General Welfare Department of North Khorasan Province

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Benign:4

Mar 28, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Nov 19, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Apr 03, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Uncertain	0.53	D;.;.;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.68	T;T;T;T;T
MetaRNN	Benign	9.3e-7	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N;.;.;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.48	N;.;.;N;.
REVEL	Uncertain	0.46
Sift	Benign	1.0	T;.;.;T;.
Sift4G	Benign	1.0	T;.;.;T;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.069
MPC		0.0040
ClinPred		0.0091	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.80
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs213950; hg19: chr7-117199533; COSMIC: COSV50040905; COSMIC: COSV50040905;